This project combines the expertise of three different investigators in an orchestrated effort to address the NCI Provocative Question #18: Are there new technologies to inhibit traditionally 'undruggable' target molecules, such as transcription factors, that are required for the oncogenic phenotype? To address this question, we will develop three distinct, but synergistic, chemistries to provide new molecules that perturb undruggable targets such as transcription factors. In concert, we will evaluate their access to targets within cells and define the structural features that code for cellular access. These concepts will be developed in the context of the p53 transcription factor, a quintessential anti-cancer target, and its effects on the MED17 subunit of the Mediator complex. PUBLIC HEALTH RELEVANCE: Transcription factors are an extremely attractive target for therapeutic intervention in cancer, however they are part of a group of molecules colloquially referred to as undruggable. This project will develop the types of new technologies needed to reach targets of this type. The initial target for study is the p53 tumor suppressor, a transcriptin factor that known as the guardian of the genome.